Opioid studies are an important area of modern medicinal chemistry research. In this study we have provided innovative considerations to some long-standing problems in opioid studies, specifically the opioid pharmacophore and the potential binding modes of opioid ligands. Based on a new peptide backbone-alignment concept that we have developed along with this study, we discuss a wide variety of opioid ligands with respect to their structureâ€“activity relationships.